Aryl and heteroaryl(phosphinylmethyl)phosphonate squalene synthetase inhibitors and method

Abstract

Phosphonic acid squalene synthetase inhibitors are provided which are effective in lowering serum cholesterol and have the formula ##STR1## wherein m is 0 to 3, n is 1 to 5, Y 1 and Y 2 are H or halogen, R 2 , R 3 and R 4 are H, metal ion, C 1 to C 8 alkyl, C 3 to C 12 alkenyl, or prodrug ester, and R 1 is a substituted or unsubstituted heteroaryl group or a substituted phenyl group.

What is claimed is: 
     
       1. A compound having the structure ##STR61## wherein m is 0, 1, 2 or 3; n is 1, 2, 3, 4 or 5; Y 1  and Y 2  are H or halogen; R 2 , R 3  and R 4  may be the same or different and are independently H, metal ion, C 1  to C 8  alkyl, C 3  to alkenyl, or prodrug ester; and   R 1  is a substituted or unsubstituted heteroaryl group linked directly to (CH 2 ) n  or indirectly to (CH 2 ) n  through an alkylene, alkenylene or alkynylene linking group, and including a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein heteroaryl is furanyl or thiofuranyl, and heteroaryl is optionally substituted with 1 to 3 groups selected from alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, aryloxy, hydroxy, halogen, nitro, amino, thiol, alkylthio, arylthio, arylsulfinyl, alkylsulfinyl, arylsulfonyl, alkylsulfonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyl, arylcarbonylamino or alkylcarbonylamino.   
     
     
       2. The compound as defined in claim 1 wherein R 1  is R 5  --Q--Y-- or R 5  --Y--Q wherein Y represents a substituted heteroaryl group; Q is an alkylene linking group, an alkylene linking group or an alkynylene linking group or a single bond;   R 5  is hydrogen, alkyl, alkenyl or alkynyl, or a pharmaceutically acceptable salt thereof.   
     
     
       3. The compound as defined in claim 1 wherein R 1  is substituted furanyl, substituted thiofuranyl, substituted pyridinyl or substituted pyrrolyl. 
     
     
       4. The compound as defined in claim 2 wherein Q is ##STR62## or a single bond, wherein t is 0, 1, 2 or 3, and x is 0, 1, 2 or 3; R 6  is H, lower alkyl, halo or haloalkyl; R 7  is H, halogen, lower alkyl or alkylthio; R 8  is H, halogen, trimethylsilyl or lower alkyl; and R 9  is H or lower alkyl; R 5  is H, ##STR63## or where R 16  is H or lower alkyl; q is 0, 1, 2, 3, 4 or 5; R 10  and R 11  are the same or different and are independently H, lower alkyl, haloalkyl, halogen or lower alkenyl or R 10  and R 11  can be taken together to form (CH 2 ) s  where s is an integer from 2 to 7; R 12  is H, lower alkyl, halogen or lower alkenyl; and R 13  and R 14  are the same or different and are independently lower alkyl. 
     
     
       5. The compound as defined in claim 4 wherein R 1  is ##STR64## wherein X is O or S and R 16a  and R 17  are the same or different and are H, alkyl containing 1 to 40 carbons, alkoxy containing 1 to 40 carbons, alkenyl containing 2 to 40 carbons, alkenyloxy containing 2 to 40 carbons, alkynyl containing 2 to 40 carbons, alkynyloxy, aryloxy, hydroxy, halogen, nitro, amino, thiol, alkylthio, arylthio, arylsulfinyl, alkylsulfinyl, arylsulfonyl, alkylsulfonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyl, arylcarbonylamino or alkylcarbonylamino. 
     
     
       6. The compound as defined in claim 2 wherein R 1  is ##STR65## wherein X is O or S; q is 0 to 5; R 10  and R 11  are independently hydrogen, lower alkyl, halogen, lower alkenyl or haloalkyl, or R 10  and R 11  can be taken together to form (CH 2 ) s , where s is 2 to 7; R 12  is hydrogen, lower alkyl, halogen or lower alkenyl; R 13  and R 14  are independently lower alkyl; R 16a  and R 17  are the same or different and are H, alkyl, containing 1 to 40 carbons, alkoxy containing 1 to 40 carbons, alkenyl containing 2 to 40 carbons, alkenyloxy containing 2 to 40 carbons, alkynyl containing 2 to 40 carbons, alkynyloxy, aryloxy, hydroxy, halogen, nitro, amino, thiol, alkylthio, arylthio, arylsulfinyl, alkylsulfinyl, arylsulfonyl, alkylsulfonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyl, arylcarbonylamino or alkylcarbonylamino.   
     
     
       7. The compound as defined in claim 1 wherein R 1  is substituted with at least one substituent which is alkyl or alkenyl. 
     
     
       8. The compound as defined in claim 7 wherein R 1  includes a second substituent which is alkyl. 
     
     
       9. The compound as defined in claim 2 wherein R 5  --Q--Y-- is ##STR66## wherein R 5  is ##STR67## R 16a  is H or alkyl and R 17  is H. 
     
     
       10. The compound as defined in claim 2 wherein R 5  --Q--Y is ##STR68## wherein R 5  is ##STR69## R 16a  is H or alkyl and R 17  is H. 
     
     
       11. The compound as defined in claim 2 wherein Y 1  and Y 2  are each F. 
     
     
       12. The compound as defined in claim 2 wherein Y 1  and Y 2  are each H. 
     
     
       13. The compound as defined in claim 2 wherein m is 1 or 2 and n is 1 or 2. 
     
     
       14. The compound as defined in claim 2 wherein n is 1, m is 1, Y 1  and Y 2  are H. 
     
     
       15. The compound as defined in claim 2 wherein one or more of R 2 , R 3  and R 4  are an alkali metal salt or alkaline earth metal salt. 
     
     
       16. The compound as defined in claim 2 wherein R 2 , R 3  and R 4  are each H. 
     
     
       17. The compound as defined in claim 2 where one or more of R 2 , R 3  and R 4  are lower alkyl or lower alkenyl. 
     
     
       18. A hypocholesterolemic or hypolipemic composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor.